- Email: [email protected]
Conjunctival squamous-cell carcinoma associated with HIV infection in Kampala, Uganda
and interpretations; and Dr K Takeda for reading the manuscript. This work was supported by a grant from the Association Francaise contre les
Myopathies. References Brzustowicz LM, Lehner T, Castilla LH, et al. Genetic mapping of chronic childhood-onset spinal muscular atrophy to chromosome 5q11.2-13.3. Nature 1990; 344: 540-41. 2 Melki J, Lefebvre S, Burglen L, et al. De novo and inherited deletions of the 5q13 region in spinal muscular atrophies. Science 1994; 264: 1474-77. 3 Henderson CE, Fardeau M. Les facteurs de croissance nerveuse: une hypothèse sur leur rôle dans la pathogénie des amyotrophies, spinales infantiles. Rev Neurol 1988; 144: 730-36, 4 Askanas V, Kwan H, Alvarez R, et al. De novo neuromuscular junction formation on human muscle fibres cultures in monolayer and innervated by fetal rat spinal cord: ultrastructural and ultrastructuralcytochemical studies. J Neurocytol 1987; 16: 523-37. 5 Askanas V, Engel WK. Cultures normal and genetically abnormal muscle. Handbook Clin Neurol 1992; 18: 85-115. 1
After (mean, SE) *1.5 (0-5). t2-3 (0-3) weekly. Muscles that underwent biopsy varied within each group (mainly biceps, deltoid, gastrocnemius, latissimus dorsis, pectineus, rectus abdominis). ALS=amyotrophic lateral sclerosis, FSH=facio scapulo humeral.
Table:
Subjects’ details and
nerve-muscle co-culture behaviour
eventually detached from culture dishes, leaving poorly filled areas of innervated muscle fibres (figure, B). The corrected/global surface ratios of the degenerating co-cultures decreased at 4 weeks. Mean (SE) ratio was 20-9% (1-8) in degenerating co-cultures and 38-6% (5-4) t test; n=5 and in non-degenerating co-cultures (p<005, 9, respectively). For this study, SMA co-cultures were from 2 SMA type I and 3 SMA type II patients, whereas non-SMA co-cultures were from 2 age-matched healthy donors and from 2 patients with Parkinson’s disease, 2 with myalgia, 1 with amyotrophic lateral sclerosis, and 2 with FSH myopathy. During the 6-8 weeks of life of aneural and non-innervated myofibres, no apparent degeneration of SMA myotubes cultures was observed. The characteristic degeneration phase was found only in innervated SMA cultures. Vacuolisation is not found in SMA muscle fibres in vivo. In other diseases, in-vitro cultures of abnormal muscle cells can result in amplification of various phenotypic patterns. Vacuoles may also only reflect a state of trauma of cultured cells. Initially, myotubes deriving from SMA satellite cells do not prevent normal rat motoneurons from reaching and innervating their target. The second-phase degeneration is not related to the muscular localisation of the biopsies and may be linked to the severity of the disease, since no abnormal behaviour of the co-cultures involving type III SMA cells was seen. Our data suggest that, after establishment of contact between nerve and skeletal muscle, the crucial dialogue between the two components is impaired. The molecular origin of the factor(s) involved (including production of a toxic factor, lack of production of trophic molecules, or alteration of recognition processes) remains to be elucidated. Our study suggests that there is an intrinsic abnormality of SMA muscle, lending support to the hypothesis of a muscular component of SMA, which may provide new insights into future therapies. We thank Dr J-H Di Donato, Prof Dubousset, Prof Y Kempf, Dr D Chaigne, A Menget, and Dr C Karger for supplying the muscle biopsy specimens; Prof M Fabre and Dr M Mohr for electronmicroscopy
Département d’Immunologie et d’Immunopharmacologie, UFR des Sciences Pharmaceutiques, Université Louis Pasteur de Strasbourg, BP 24, 67401 Illkirch Cedex, France (S Braun PhD, Prof J M Warter MD, Prof P Poindron PhD); and Association Française contre les Myopathies, Paris, France (B Croizat PhD, M C Lagrange PhD) Correspondence to: Prof Philippe Poindron
Conjunctival squamous-cell carcinoma associated with HIV infection in Kampala, Uganda
The incidence of conjunctival squamous-cell carcinoma in Kampala, Uganda, was steady at around 6 per million per year from 1970 until 1988, but has increased six-fold since then to 35 per million per year in 1992. Among 48 patients with conjunctival tumours seen at the ophthalmology clinic of the New Mulago Hospital from 1990 to 1991, 75% were HIV seropositive, compared with a 19% seropositivity rate among 48 matched controls (relative risk 13·0, 95% Cl 4·5-39·4, p<0·0001). The recent epidemic of conjunctival tumours in Uganda (and in neighbouring countries) appears to be largely due to the epidemic of HIV infection. Other factors that may contribute to the high incidence of these tumours in equatorial Africa may be exposure to ultraviolet light and conjunctival papillomavirus infection. Lancet
1995; 345: 695-96
After two case-reports of conjunctival squamous-cell carcinoma in HIV seropositive males in the USA,’2 Kestelyn et aP noted an increase in patients attending their ophthalmology clinic in Kigali, Rwanda, with conjunctival tumours: HIV seropositivity was 82% in 11 patients with these tumours and 27% in 22 controls matched for age and sex. We have also seen an increase in conjunctival cancers in patients attending the New Mulago Hospital in Kampala, Uganda. This finding is supported by statistics from the Kampala Cancer Registry, which show that the incidence of conjunctival squamous-cell carcinoma was steady at 6 per million per 695
Figure 2: Conjunctival squamous-cell carcinomas in 2 HIVpositive subjects et a13 from Rwanda, and indicate that in certain of Africa there has been a recent increase in the parts of conjunctival tumours associated with the frequency 1: rates of Annual incidence HIV Figure conjunctival squamous-cell epidemic. The relative risk for conjunctival tumours carcinoma of eye in Kampala district associated with HIV infection was 13.0 in this study and Number of cases shown. 11 -0 in that of Kesterlyn and colleagues. In both studies, the subjects were young and the tumours were aggressive. From the scarcity of case reports, such tumours may be year from 1970 until 1988, and has increased six-fold uncommon in HIV-infected subjects from the USA or since (figure 1). If Between February, 1990, and February, 1991, all patients with Europe. so, this would reflect the underlying incidence of these tumours before the AIDS epidemic. Before the conjunctival growths who presented to the ophthalmology clinic had an excision biopsy, and blood was taken for HIV testing by 1980s, the incidence of conjunctival squamous-cell ELISA and confirmatory western blot in the 48 who had carcinoma was more common in countries in equatorial squamous-cell carcinoma. The age range was 18-56 years (mean Africa than elsewhere, and at the time exposure to 325); 24 subjects were aged 20-29 and 12 were aged 30-39 ultraviolet light was suggested as a cause.4 The human years. 25 were male. The biopsy specimens were examined in the papillomavirus type 16 has also been associated with these department of pathology at Makerere University and were tumours,5 and the combination of HIV-induced immunohistologically confirmed as invasive squamous-cell carcinoma, or carcinoma-in-situ, mucosepidermoid squamous-cell suppression, conjunctival papillomavirus infection, and intense exposure to ultraviolet light might hasten the carcinoma of the conjunctiva. Age-matched and sex-matched controls were chosen from patients attending the same clinic with development of these cancers.
Kesterlyn
other eye diseases. Informed
consent was
obtained from all
subjects.
(75%) of the 48 patients with conjunctival cancers were seropositive compared with 9 (19%) in the controls (relative risk 13-0, 95% CI 4-5-39-4, p<0-00001). 36
Most tumours arose in the limbus of the eye and the lesions in the HIV patients were aggressive: the duration of symptoms was mostly less than 3 months. Figure 2 (right) shows a limbal lesion of 1 month’s duration in a 27-year-old HIV seropositive male. Histological examination revealed a well-differentiated conjunctival squamous-cell carcinoma. Figure 2 (left) shows a conjunctival tumour in a 30-year-old HIV seropositive female. The tumour started as a whitish swelling in the limbus 2 months previously and rapidly increased in size. Histological examination revealed a poorly differentiated squamous-cell carcinoma. These findings agree closely with those reported by
696
References 1 Winward KE, Curtin VT. Conjunctival squamous cell carcinoma in patient with human immunodeficiency virus infection. Am J
a
Ophthalmol 1989; 107: 554-55. Kim RY, Seiff DR, Howes EL Jr, O’Donnell JJ. Necrotizing scleritis secondary to conjunctival squamous cell carcinoma in acquired immunodeficiency syndrome. Am J Ophthalmol 1990; 109: 231-33. 3 Kestelyn Ph, Stevens A-M, Ndayambaje A, Hanssens M, van de Perre Ph. HIV and conjunctival malignancies. Lancet 1990; 336: 51-52. 4 Tumours of the eye and adnexa. In: Templeton AC, ed. Tumours of a tropical country: a survey of Uganda 1964-1968. Recent Results Cancer Res 1973; 43: 203-14. 5 Tritten JJ et al. Bilateral conjunctival and eyelid tumour associated with human papillomavirus in an immunocompetent man. Klin Monatsbl Augenheilikd 1994; 204: 453-55. 2
Department of Ophthalmology, Makerere University Medical School, PO Box 7022, Kampala, Uganda (C Ateenyi-Agaba MB)
Myopathies. References Brzustowicz LM, Lehner T, Castilla LH, et al. Genetic mapping of chronic childhood-onset spinal muscular atrophy to chromosome 5q11.2-13.3. Nature 1990; 344: 540-41. 2 Melki J, Lefebvre S, Burglen L, et al. De novo and inherited deletions of the 5q13 region in spinal muscular atrophies. Science 1994; 264: 1474-77. 3 Henderson CE, Fardeau M. Les facteurs de croissance nerveuse: une hypothèse sur leur rôle dans la pathogénie des amyotrophies, spinales infantiles. Rev Neurol 1988; 144: 730-36, 4 Askanas V, Kwan H, Alvarez R, et al. De novo neuromuscular junction formation on human muscle fibres cultures in monolayer and innervated by fetal rat spinal cord: ultrastructural and ultrastructuralcytochemical studies. J Neurocytol 1987; 16: 523-37. 5 Askanas V, Engel WK. Cultures normal and genetically abnormal muscle. Handbook Clin Neurol 1992; 18: 85-115. 1
After (mean, SE) *1.5 (0-5). t2-3 (0-3) weekly. Muscles that underwent biopsy varied within each group (mainly biceps, deltoid, gastrocnemius, latissimus dorsis, pectineus, rectus abdominis). ALS=amyotrophic lateral sclerosis, FSH=facio scapulo humeral.
Table:
Subjects’ details and
nerve-muscle co-culture behaviour
eventually detached from culture dishes, leaving poorly filled areas of innervated muscle fibres (figure, B). The corrected/global surface ratios of the degenerating co-cultures decreased at 4 weeks. Mean (SE) ratio was 20-9% (1-8) in degenerating co-cultures and 38-6% (5-4) t test; n=5 and in non-degenerating co-cultures (p<005, 9, respectively). For this study, SMA co-cultures were from 2 SMA type I and 3 SMA type II patients, whereas non-SMA co-cultures were from 2 age-matched healthy donors and from 2 patients with Parkinson’s disease, 2 with myalgia, 1 with amyotrophic lateral sclerosis, and 2 with FSH myopathy. During the 6-8 weeks of life of aneural and non-innervated myofibres, no apparent degeneration of SMA myotubes cultures was observed. The characteristic degeneration phase was found only in innervated SMA cultures. Vacuolisation is not found in SMA muscle fibres in vivo. In other diseases, in-vitro cultures of abnormal muscle cells can result in amplification of various phenotypic patterns. Vacuoles may also only reflect a state of trauma of cultured cells. Initially, myotubes deriving from SMA satellite cells do not prevent normal rat motoneurons from reaching and innervating their target. The second-phase degeneration is not related to the muscular localisation of the biopsies and may be linked to the severity of the disease, since no abnormal behaviour of the co-cultures involving type III SMA cells was seen. Our data suggest that, after establishment of contact between nerve and skeletal muscle, the crucial dialogue between the two components is impaired. The molecular origin of the factor(s) involved (including production of a toxic factor, lack of production of trophic molecules, or alteration of recognition processes) remains to be elucidated. Our study suggests that there is an intrinsic abnormality of SMA muscle, lending support to the hypothesis of a muscular component of SMA, which may provide new insights into future therapies. We thank Dr J-H Di Donato, Prof Dubousset, Prof Y Kempf, Dr D Chaigne, A Menget, and Dr C Karger for supplying the muscle biopsy specimens; Prof M Fabre and Dr M Mohr for electronmicroscopy
Département d’Immunologie et d’Immunopharmacologie, UFR des Sciences Pharmaceutiques, Université Louis Pasteur de Strasbourg, BP 24, 67401 Illkirch Cedex, France (S Braun PhD, Prof J M Warter MD, Prof P Poindron PhD); and Association Française contre les Myopathies, Paris, France (B Croizat PhD, M C Lagrange PhD) Correspondence to: Prof Philippe Poindron
Conjunctival squamous-cell carcinoma associated with HIV infection in Kampala, Uganda
The incidence of conjunctival squamous-cell carcinoma in Kampala, Uganda, was steady at around 6 per million per year from 1970 until 1988, but has increased six-fold since then to 35 per million per year in 1992. Among 48 patients with conjunctival tumours seen at the ophthalmology clinic of the New Mulago Hospital from 1990 to 1991, 75% were HIV seropositive, compared with a 19% seropositivity rate among 48 matched controls (relative risk 13·0, 95% Cl 4·5-39·4, p<0·0001). The recent epidemic of conjunctival tumours in Uganda (and in neighbouring countries) appears to be largely due to the epidemic of HIV infection. Other factors that may contribute to the high incidence of these tumours in equatorial Africa may be exposure to ultraviolet light and conjunctival papillomavirus infection. Lancet
1995; 345: 695-96
After two case-reports of conjunctival squamous-cell carcinoma in HIV seropositive males in the USA,’2 Kestelyn et aP noted an increase in patients attending their ophthalmology clinic in Kigali, Rwanda, with conjunctival tumours: HIV seropositivity was 82% in 11 patients with these tumours and 27% in 22 controls matched for age and sex. We have also seen an increase in conjunctival cancers in patients attending the New Mulago Hospital in Kampala, Uganda. This finding is supported by statistics from the Kampala Cancer Registry, which show that the incidence of conjunctival squamous-cell carcinoma was steady at 6 per million per 695
Figure 2: Conjunctival squamous-cell carcinomas in 2 HIVpositive subjects et a13 from Rwanda, and indicate that in certain of Africa there has been a recent increase in the parts of conjunctival tumours associated with the frequency 1: rates of Annual incidence HIV Figure conjunctival squamous-cell epidemic. The relative risk for conjunctival tumours carcinoma of eye in Kampala district associated with HIV infection was 13.0 in this study and Number of cases shown. 11 -0 in that of Kesterlyn and colleagues. In both studies, the subjects were young and the tumours were aggressive. From the scarcity of case reports, such tumours may be year from 1970 until 1988, and has increased six-fold uncommon in HIV-infected subjects from the USA or since (figure 1). If Between February, 1990, and February, 1991, all patients with Europe. so, this would reflect the underlying incidence of these tumours before the AIDS epidemic. Before the conjunctival growths who presented to the ophthalmology clinic had an excision biopsy, and blood was taken for HIV testing by 1980s, the incidence of conjunctival squamous-cell ELISA and confirmatory western blot in the 48 who had carcinoma was more common in countries in equatorial squamous-cell carcinoma. The age range was 18-56 years (mean Africa than elsewhere, and at the time exposure to 325); 24 subjects were aged 20-29 and 12 were aged 30-39 ultraviolet light was suggested as a cause.4 The human years. 25 were male. The biopsy specimens were examined in the papillomavirus type 16 has also been associated with these department of pathology at Makerere University and were tumours,5 and the combination of HIV-induced immunohistologically confirmed as invasive squamous-cell carcinoma, or carcinoma-in-situ, mucosepidermoid squamous-cell suppression, conjunctival papillomavirus infection, and intense exposure to ultraviolet light might hasten the carcinoma of the conjunctiva. Age-matched and sex-matched controls were chosen from patients attending the same clinic with development of these cancers.
Kesterlyn
other eye diseases. Informed
consent was
obtained from all
subjects.
(75%) of the 48 patients with conjunctival cancers were seropositive compared with 9 (19%) in the controls (relative risk 13-0, 95% CI 4-5-39-4, p<0-00001). 36
Most tumours arose in the limbus of the eye and the lesions in the HIV patients were aggressive: the duration of symptoms was mostly less than 3 months. Figure 2 (right) shows a limbal lesion of 1 month’s duration in a 27-year-old HIV seropositive male. Histological examination revealed a well-differentiated conjunctival squamous-cell carcinoma. Figure 2 (left) shows a conjunctival tumour in a 30-year-old HIV seropositive female. The tumour started as a whitish swelling in the limbus 2 months previously and rapidly increased in size. Histological examination revealed a poorly differentiated squamous-cell carcinoma. These findings agree closely with those reported by
696
References 1 Winward KE, Curtin VT. Conjunctival squamous cell carcinoma in patient with human immunodeficiency virus infection. Am J
a
Ophthalmol 1989; 107: 554-55. Kim RY, Seiff DR, Howes EL Jr, O’Donnell JJ. Necrotizing scleritis secondary to conjunctival squamous cell carcinoma in acquired immunodeficiency syndrome. Am J Ophthalmol 1990; 109: 231-33. 3 Kestelyn Ph, Stevens A-M, Ndayambaje A, Hanssens M, van de Perre Ph. HIV and conjunctival malignancies. Lancet 1990; 336: 51-52. 4 Tumours of the eye and adnexa. In: Templeton AC, ed. Tumours of a tropical country: a survey of Uganda 1964-1968. Recent Results Cancer Res 1973; 43: 203-14. 5 Tritten JJ et al. Bilateral conjunctival and eyelid tumour associated with human papillomavirus in an immunocompetent man. Klin Monatsbl Augenheilikd 1994; 204: 453-55. 2
Department of Ophthalmology, Makerere University Medical School, PO Box 7022, Kampala, Uganda (C Ateenyi-Agaba MB)